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Liraglutide, a Glucagon-like Peptide-1 Receptor Agonist, Attenuates Development of Cardiac Allograft Vasculopathy in a Murine Heart Transplant Model

Wang, ZhiMin, PhD1; Wang, Mengjun, MD1; Hu, Xiaofan, PhD2; Li, Yakun, MD1; Ma, DongXia, PhD3; Li, ShangLin, MD1; Zhao, GuangYuan, PhD1; Xie, YaNan, MD1; Shu, Yanwen, PhD2; Yang, Jun, PhD1

doi: 10.1097/TP.0000000000002448
Original Basic Science—General
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Background. Advances in immunosuppressive therapy have significantly improved short-term but not long-term survival of cardiac transplant recipients; this is largely due to severe cardiac allograft vasculopathy (CAV). Glucagon-like peptide-1 receptor (GLP-1R)-based therapy exerts physiological effects on the cardiovascular system in addition to its traditional role in controlling glucose. We have investigated the effects of liraglutide, a GLP-1R agonist, on the development of CAV in a murine heart transplant model.

Methods. Heterotopic murine cardiac transplantation was performed with a major histocompatibility complex class II-mismatched model. Recipient mice were subcutaneously administered vehicle (0.9% saline solution) or liraglutide (300 μg·kg−1 every 12 hours) from the day of transplantation. Allografts were harvested at 2 or 8 weeks and histologically analyzed. Inflammatory infiltrates were measured by immunohistochemistry, and immunofluorescence and western blotting analyzes were used to evaluate GLP-1R expression and markers of endothelial-to-mesenchymal transition (EndMT) in cardiac allografts and human coronary artery endothelial cells challenged with transforming growth factor-beta 1.

Results. Glucagon-like peptide-1 receptor was predominantly localized to vascular endothelial cells and was upregulated in cardiac allografts after liraglutide treatment. Liraglutide ameliorated CAV and cardiac fibrosis with reduced inflammatory cell infiltration and downregulated expression of adhesion molecules. Liraglutide inhibited EndMT in allografts and attenuated EndMT by inhibiting Smad3 activation in transforming growth factor-beta 1–treated human coronary artery endothelial cells.

Conclusions. Administration of liraglutide from the time of transplantation upregulated GLP-1R in the transplanted heart and reduced cardiac fibrosis, inflammation, and CAV development. Therefore, liraglutide may be a novel therapy for CAV.

1Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Key Laboratory of Organ Transplantation, Ministry of Education, Key Laboratory of Organ Transplantation, Ministry of Health, Wuhan, China.

2Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

3Department of Allergy, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

Received 5 July 2018. Revision received 15 August 2018.

Accepted 5 September 2018.

The authors declare no conflicts of interest.

The study was supported by the National Nature Science Foundation of China (no. 81373169 to J.Y.).

J.Y, Z.-M.W., and Y.-W.S. conceived and designed the experiments. Z.-M.W., X.-F.H., Y.-K.L., D.-X.M., G.-Y.Z., M.-J.W., and Y.-N.X. performed the experiments. J.Y., Z.-M.W. and X.-F.H. analyzed the data. J.Y. and Z.-M.W. wrote the article.

Supplemental digital content (SDC) is available for this article. Direct URL citations appear in the printed text, and links to the digital files are provided in the HTML text of this article on the journal’s Web site (www.transplantjournal.com).

Correspondence: Yan-wen Shu, PhD, Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 JieFang Ave, Wuhan 430022, China. (shuyanwen@yahoo.com); Jun Yang, PhD, Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1095 Jiefang Rd, Wuhan 430030, Hubei Province, China. (jy@tjh.tjmu.edu.cn).

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